Although hormone replacement therapy has been associated with reduction of cardiovascular events in postmenopausal women, the mechanisms that mediate this apparent benefit are unclear. Because improvement in blood vessel function may represent one of the beneficial effects of estrogen administration, we sought to investigate the acute effects of physiologic levels of estrogen on the vascular responses of estrogen-deficient postmenopausal women. The study included 40 postmenopausal women aged 60plus/minus8 years (mean plus/minusSD), 20 of whom had one or more conditions associated with vascular dysfunction (hypertension, hypercholesterolemia, diabetes mellitus or coronary artery disease). The forearm vascular responses to the endothelium-dependent vasodilator acetylcholine were studied before and during infusion of 17beta-estradiol into the ipsilateral brachial artery. In 31 subjects the effect of estradiol on the responses to the endothelium-independent vasodilator sodium nitroprusside was also studied. Women with risk factors for vascular dysfunction had significantly reduced vasodilator responses to acetylcholine and to sodium nitroprusside compared with healthy subjects. Intra-arterial infusion of 17beta-estradiol increased the forearm venous estradiol concentration from 16q10 pg/ml to 318plus/minus188 pg/ml, levels typical of reproductive aged women at midcycle. Estradiol infusion potentiated the forearm vasodilation induced by acetylcholine by 18% in women with risk factors for vascular dysfunction and by 20% in healthy women, both statistically significant responses. Estradiol also potentiated the forearm vasodilation induced by sodium nitroprusside in women with risk factors for vascular dysfunction by 14%, also a significant potentiation. We concluded that physiologic levels of 17beta-estradiol selectively potentiates endothelium-dependent vasodilation in healthy postmenopausal women, and potentiates both endothelium-dependent and endothelium-independent vasodilation in postmenopausal women with risk factors for atherosclerosis and evidence of impaired vascular function.